Cirrhosis caused by nonalcoholic steatohepatitis (NASH) is common and life threatening. Gaps in knowledge about myofibroblasts, the fibrogenic cells that drive cirrhosis pathogenesis styme treatment of NASH-cirrhosis. In NASH-cirrhosis, myofibroblasts derive from resident stellate cells. We discovered that: 1) stellate cells must induce and maintain Hedgehog signaling to be myofibroblastic, 2) persistent Hedgehog activity causes progressive fibrosis, and 3) transient Hedgehog activation is necessary for liver regeneration. Hedgehog must be induced, and then suppressed, for recovery from NASH. Identifying the mechanisms which regulate Hedgehog signaling is imperative for defining novel therapeutic targets to reverse hepatic fibrosis. Herein, we evaluate a novel HYPOTHESIS that interaction of pleiotrophin (a myofibroblast-derived factor that promotes regeneration) and its receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), prevents NASH- cirrhosis by antagonizing Hedgehog's pro-fibrogenic actions in myofibroblasts. Recently, we discovered that degregulation of pleiotrophin-Hedgehog signaling in PTPRZ1-expressing stellate cells might contribute to cirrhosis pathogenesis in NASH. Specifically, we found that livers with NASH are enriched with PTPRZ1(+) cells and showed that pleiotrophin antagonizes key actions of Hedgehog by studying pleiotrophin- and PTPRZ1-knockout mice. Studies in cultured stellate cells indicated that the mechanism is indirect and involves pleiotrophin-dependent inhibition of PTPRZ1's phosphatase activity, alteration of the phosphoproteome, and consequent changes in the cellular localization of Yes-activated peptide (YAP), a Hippo kinase-regulated transcriptional co-activator that controls liver growth. We propose a novel paradigm whereby myofibroblast fate is controlled by factors, such as Hedgehog and pleiotrophin, that modulate activation/inactivation of YAP. Our SPECIFIC AIMS are to: 1) determine how pleiotrophin inhibits Hedgehog activity in myofibroblasts and 2) determine how pleiotrophin-mediated inhibition of Hedgehog in myofibroblasts inhibits NASH cirrhosis. Successful completion of this proposal will identify new therapeutic targets for NASH cirrhosis and fill a gap in knowledge about the regulation of fibrotic liver injury.